Prion diseases are transmissible and fatal neurodegenerative diseases of animals and humans. The pathogenic mechanism of prion-induced neurotoxicity is not well defined, but it is proposed that either the loss of cellular prio protein (PrPC) function or gain of toxic function of PrPC and/or PrPSc plays a significant role in neurodegeneration. In this exploratory study we will examine the contribution of PrPC-mediated Fyn activation to the pathogenesis of prion disease. Fyn is an important regulator of synaptogenesis; under normal physiological conditions synapse formation can be dynamic, while during disease certain conditions can induce synaptic loss through the Fyn pathway. We propose that PrPC-mediated Fyn activation can cause neurotoxicity in prion neurodegeneration by either disruption of neuronal maturation and/or the loss of mature neurons. To test this hypothesis we will examine events upstream of PrPC signal transduction and monitor protein-protein interactions that regulate this pathway during prion neurodegeneration in olfactory sensory neurons (OSNs). This is an ideal system to investigate the role of PrPC in neurodegeneration because OSNs undergo continuous maturation in adults, but during prion infection there is reduced survival of OSNs. Analysis of proteins that bind to PrPC to initiate signal transduction, and the phosphorylation status of Fyn, can indicate the role of PrPC and Fyn activation in prion neurotoxicity. The second aim will be to determine whether prion infection blocks OSN maturation and to examine the status of PrPC-mediated Fyn activation during neuronal maturation and in differentiated OSNs. These studies will measure cell proliferation and survival of neurons in the olfactory epithelium to determine if neuronal maturation is inhibited or unimpeded. The third aim will investigate the effect of altered OSN axon targeting on neuron viability during prion neurodegeneration by measuring OSN synapses in glomeruli in the olfactory bulb and OSN cell bodies in the olfactory epithelium. This analysis will determine the role of OSN structural deficits on synapse formation and neuron survival during prion infection. Given the central role PrPC plays in both normal development and disease, in addition to its importance in PrPSc formation, understanding the role of PrPC in signal transduction pathways could reveal therapeutic targets to treat or prevent neurodegenerative diseases.